Small deep infarcts (SDI) including lacunar stroke account for greater than one quarter of all ischemic strokes. Though SDI cause the smallest amount of brain injury of all stroke subtypes, long-term outcomes are significant with 42% of lacunar stroke patients being dependent by 3 years (Samuelsson et al., Stroke (1996) 27(5):842-6; Lee, et al., Int J Cardiol. (2009) Mar. 25; Giroud, et al, Rev Neurol (Paris). (1991) 147(8-9):566-72; Clavier, et al., Stroke. (1994) 25(10):2005-9; Carod-Artal, et al., Stroke. (2005) 36(5):965-70). Indeed, lacunar strokes are indicative of cardiovascular disease with an annual death rate of 2.8% and an increased risk of recurrent stroke, white matter disease and cognitive impairment (Samuelsson, et al., supra; Norrving, Lancet Neurol. (2003) 2(4):238-45; Jackson, et al., Brain. (2005) 128(Pt 11):2507-17).
The term lacune was first used to describe small subcortical infarctions in the 1800s by Dechambre and Durand-Fardel. In the 1960s Miller Fisher described the lacunar hypothesis, correlating the clinical symptoms of lacunar syndromes with pathologic findings of single perforating branch occlusion from microatheroma or lipohyalinosis (Fisher, Acta Neuropathol. (1968) 12(1):1-15; Fisher, Neurology (1965) 15:774-84; Fisher, Neurology (1982) 32(8):871-6; and Bamford and Warlow, Stroke. (1988) 19(9):1074-82). The lacunar hypothesis distinguishes lacunar stroke from other causes of SDI, including disease of the parent artery and embolism of arterial or cardiac origin. Determining whether an SDI is of small vessel lacunar or non-small vessel etiology remains a topic of controversy and investigation (Millikan, et al., Stroke (1990) 21(9):1251-7; Futrell, Stroke (2004) 35(7):1778-9; Norrving, Stroke (2004) 35(7):1779-80; Davis and Donnan, Stroke (2004) 35(7):1780-1; and Maron, et al., J Am Coll Cardiol. (2002) 39(2):301-7). An embolic cause of stroke warrants a different investigative strategy and treatment than other ischemic stroke syndromes. In particular, it is important to diagnose disease that would change management, such as carotid surgery for symptomatic carotid stenosis and warfarin for symptomatic atrial fibrillation. Therefore, ascertaining the etiology of SDI is not only of academic interest but also of clinical significance.
The presence of a potential cardioembolic or arterial embolic source does not necessarily imply a causal association with SDI. Indeed, most of the vascular risk factors associated with lacunar infarction are also those that predispose to arterial and cardioembolic disease. Several predictors have been identified to suggest an SDI is of lacunar etiology. The clinical features of a lacunar syndrome predict infarcts that are radiological findings consistent with lacunar stroke (Gan, et al., Neurology (1997) 48(5):1204-11; and Lee, et al., Stroke (2005) 36(12):2583-8). However, lacunar syndromes can be mimicked by non-lacunar disease, such as cortical infarction, hemorrhagic stroke and non-vascular disease (Wessels, et al., Stroke (2005) 36(4):757-61; Arboix, et al., BMC Neurol. (2010) 10:31). Furthermore, infarction in the regions of the penetrating arteries (basal ganglia, thalamus, internal capsule, corona radiata and pons) can result from non-lacunar disease, including disease of the parent artery and emboli of arterial or cardiac origin. Infarct diameter<15 mm is also predictive of lacunar stroke, since this is the approximate vascular territory of a single penetrating artery (Bang, et al., Cerebrovasc Dis. (2007) 24(6):520-9; Cho, et al., Cerebrovasc Dis. (2007) 23(1):14-9; and Lodder, Cerebrovasc Dis. (2007) 24(1):156-7). However, in patients with SDI>15 mm in size or with a coincidental arterial or cardioembolic source, it remains less clear as to whether a stroke is of lacunar or non-lacunar etiology.
The present invention is based, in part, on using gene expression profiling to distinguish patients who have suffered or are at risk of suffering lacunar stroke from patients who have suffered or are at risk of suffering embolic strokes using a gene expression profiling. The gene expression profiles further find use to predict the cause of stroke in SDI of unclear cause (SDI size>15 mm or SDI with potential embolic source). It has recently been demonstrated that cardioembolic and large vessel causes of stroke have unique gene expression signatures (Jickling, et al., Ann Neurol. (2010) 68(5):681-92; and Xu, et al., J Cereb Blood Flow Metab. (2008) 28(7):1320-8). These signatures can be used to categorize, diagnose and treat stroke patients by cause based on a profile of differentially expressed genes. The identified genes were predominantly expressed in inflammatory cells associated with each stroke subtype. The present invention is based, in part, on the identification of a profile of differentially expressed genes useful to distinguish lacunar stroke from non-lacunar stroke and to predict etiology in SDI of unclear cause.